2. Academic Validation
  3. Novel Oxazolidinone-Based Peroxisome Proliferator Activated Receptor Agonists: Molecular Modeling, Synthesis, and Biological Evaluation

Novel Oxazolidinone-Based Peroxisome Proliferator Activated Receptor Agonists: Molecular Modeling, Synthesis, and Biological Evaluation

  • J Med Chem. 2015 Aug 27;58(16):6639-52. doi: 10.1021/acs.jmedchem.5b00849.
N Fresno 1,  M Macías-González 2 3,  A Torres-Zaguirre 1,  M Romero-Cuevas 2 3,  P Sanz-Camacho 1,  J Elguero 1,  F J Pavón 2 3,  F Rodríguez de Fonseca 2 3,  P Goya 1,  R Pérez-Fernández 1 4
Affiliations

Affiliations

  • 1 Instituto de Química Médica, Consejo Superior de Investigaciones Científicas (IQM-CSIC) , Juan de la Cierva 3, E-28006 Madrid, Spain.
  • 2 Centros de Investigación En Red (CIBER) Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III , CB06/03, E-28029, Madrid, Spain.
  • 3 Unidad Gestión Clínica Endocrinología y Nutrición, Instituto de Investigación Biomédica de Málaga (IBIMA), Hospitales Universitarios Regional y Virgen de la Victoria de Málaga, Universidad de Málaga , E-29071 Málaga, Spain.
  • 4 Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas (CIB-CSIC) , Ramiro de Maeztu 9, E-28040 Madrid, Spain.
PMID: 26226490 DOI: 10.1021/acs.jmedchem.5b00849
Abstract

A series of new peroxisome proliferator activated receptors (PPARs) chiral ligands have been designed following the accepted three-module structure comprising a polar head, linker, and hydrophobic tail. The majority of the ligands incorporate the Oxazolidinone moiety as a novel polar head, and the nature of the hydrophobic tail has also been varied. Docking studies using the crystal structure of an agonist bound to the ligand binding domain of the PPARα receptor have been performed as a tool for their design. Suitable synthetic procedures have been developed, and compounds with different stereochemistries have been prepared. Evaluation of basal and ligand-induced activity proved that several compounds showed agonist activity at the PPARα receptor, thus validating the Oxazolidinone template for PPAR activity. In addition, two compounds, 2 and 4, showed dual PPARα/PPARγ agonism and interesting food intake reduction in rats.

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